Strategic white matter injury associated with long‐term information processing speed deficits in mild traumatic brain injury

Deficits in information processing speed (IPS) are among the earliest and most prominent cognitive manifestations in mild traumatic brain injury (mTBI). We investigated the impact of white matter fiber location on IPS outcome in an individual basis assessment. A total of 112 acute mild TBI with all CT negative underwent brain DTI and blood sampling for inflammation cytokines within 7 days postinjury and 72 age‐ and sex matched healthy controls with same assessments were enrolled. IPS outcome was assessed by the trail making test at 6–12 month postinjury in mild TBI. Fractional anisotropy (FA) features were extracted using a novel lesion‐load analytical strategy to capture spatially heterogeneous white matter injuries and minimize implicit assumptions of uniform injury across diverse clinical presentations. Acute mild TBI exhibited a general pattern of increased and decreased FA in specific white matter tracts. The power of acute FA measures to identify patients developing IPS deficits with 92% accuracy and further improved to 96% accuracy by adding inflammation cytokines. The classifiers predicted individual's IPS and working memory ratings (r = .74 and .80, respectively, p < .001). The thalamo‐cortical circuits and commissural tracts projecting or connecting frontal regions became important predictors. This prognostic model was also verified by an independent replicate sample. Our findings highlighted damage to frontal interhemispheric and thalamic projection fiber tracts harboring frontal‐subcortical neuronal circuits as a predictor for processing speed performance in mild TBI.     

Longitudinal white matter microstructural changes in pediatric mild traumatic brain injury: An A‐CAP study

In the largest sample studied to date, white matter microstructural trajectories and their relation to persistent symptoms were examined after pediatric mild traumatic brain injury (mTBI). This prospective, longitudinal cohort study recruited children aged 8–16.99 years with mTBI or mild orthopedic injury (OI) from five pediatric emergency departments. Children''s pre‐injury and 1‐month post‐injury symptom ratings were used to classify mTBI with or without persistent symptoms. Children completed diffusion‐weighted imaging at post‐acute (2–33 days post‐injury) and chronic (3 or 6 months via random assignment) post‐injury assessments. Mean diffusivity (MD) and fractional anisotropy (FA) were derived for 18 white matter tracts in 560 children (362 mTBI/198 OI), 407 with longitudinal data. Superior longitudinal fasciculus FA was higher in mTBI without persistent symptoms relative to OI, d (95% confidence interval) = 0.31 to 0.37 (0.02, 0.68), across time. In younger children, MD of the anterior thalamic radiations was higher in mTBI with persistent symptoms relative to both mTBI without persistent symptoms, 1.43 (0.59, 2.27), and OI, 1.94 (1.07, 2.81). MD of the arcuate fasciculus, −0.58 (−1.04, −0.11), and superior longitudinal fasciculus, −0.49 (−0.90, −0.09) was lower in mTBI without persistent symptoms relative to OI at 6 months post‐injury. White matter microstructural changes suggesting neuroinflammation and axonal swelling occurred chronically and continued 6 months post injury in children with mTBI, especially in younger children with persistent symptoms, relative to OI. White matter microstructure appears more organized in children without persistent symptoms, consistent with their better clinical outcomes.     

Effects of chronic mild traumatic brain injury on white matter integrity in Iraq and Afghanistan war veterans

Mild traumatic brain injury (TBI) is a common source of morbidity from the wars in Iraq and Afghanistan. With no overt lesions on structural MRI, diagnosis of chronic mild TBI in military veterans relies on obtaining an accurate history and assessment of behavioral symptoms that are also associated with frequent comorbid disorders, particularly posttraumatic stress disorder (PTSD) and depression. Military veterans from Iraq and Afghanistan with mild TBI (n = 30) with comorbid PTSD and depression and non‐TBI participants from primary (n = 42) and confirmatory (n = 28) control groups were assessed with high angular resolution diffusion imaging (HARDI). White matter‐specific registration followed by whole‐brain voxelwise analysis of crossing fibers provided separate partial volume fractions reflecting the integrity of primary fibers and secondary (crossing) fibers. Loss of white matter integrity in primary fibers (P < 0.05; corrected) was associated with chronic mild TBI in a widely distributed pattern of major fiber bundles and smaller peripheral tracts including the corpus callosum (genu, body, and splenium), forceps minor, forceps major, superior and posterior corona radiata, internal capsule, superior longitudinal fasciculus, and others. Distributed loss of white matter integrity correlated with duration of loss of consciousness and most notably with “feeling dazed or confused,” but not diagnosis of PTSD or depressive symptoms. This widespread spatial extent of white matter damage has typically been reported in moderate to severe TBI. The diffuse loss of white matter integrity appears consistent with systemic mechanisms of damage shared by blast‐ and impact‐related mild TBI that involves a cascade of inflammatory and neurochemical events. Hum Brain Mapp 34:2986–2999, 2013. © 2012 Wiley Periodicals, Inc.     

Ethyl pyruvate improves white matter remodeling in rats after traumatic brain injury

BackgroundSevere traumatic brain injury (TBI) results in long‐term neurological deficits associated with white matter injury (WMI). Ethyl pyruvate (EP) is a simple derivative of the endogenous energy substrate pyruvate with neuroprotective properties, but its role in recovery from WMI has not been explored.AimsThis study examines the effect of EP treatment on rats following TBI using behavioral tests and white matter histological analysis up to 28 days post‐injury.Materials and MethodsAnaesthetised adult rats were subjected to TBI by controlled cortical impact. After surgery, EP or Ringers solution (RS) was administrated intraperitoneally at 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Sensorimotor deficits were evaluated up to day 21 after TBI by four independent tests. Immunofluorescence and transmission electron microscopy (TEM) were performed to assess white matter injury. Microglia activation and related inflammatory molecules were examined up to day 14 after TBI by immunohistochemistry or real‐time PCR.ResultsHere, we demonstrate that EP improves sensorimotor function following TBI as well as improves white matter outcomes up to 28 d after TBI, as shown by reduced myelin loss. Furthermore, EP administration during the acute phase of TBI recovery shifted microglia polarization toward the anti‐inflammatoryM2 phenotype, modulating the release of inflammatory‐related factors.ConclusionEP treatment may protect TBI‐induced WMI via modulating microglia polarization toward M2.     

Structural connectome differences in pediatric mild traumatic brain and orthopedic injury

Sophisticated network‐based approaches such as structural connectomics may help to detect a biomarker of mild traumatic brain injury (mTBI) in children. This study compared the structural connectome of children with mTBI or mild orthopedic injury (OI) to that of typically developing (TD) children. Children aged 8–16.99 years with mTBI (n = 83) or OI (n = 37) were recruited from the emergency department and completed 3T diffusion MRI 2–20 days postinjury. TD children (n = 39) were recruited from the community and completed diffusion MRI. Graph theory metrics were calculated for the binarized average fractional anisotropy among 90 regions. Multivariable linear regression and linear mixed effects models were used to compare groups, with covariates age, hemisphere, and sex, correcting for multiple comparisons. The two injury groups did not differ on graph theory metrics, but both differed from TD children in global metrics (local network efficiency: TD > OI, mTBI, d = 0.49; clustering coefficient: TD < OI, mTBI, d = 0.49) and regional metrics for the fusiform gyrus (lower degree centrality and nodal efficiency: TD > OI, mTBI, d = 0.80 to 0.96; characteristic path length: TD < OI, mTBI, d = −0.75 to −0.90) and in the superior and middle orbital frontal gyrus, paracentral lobule, insula, and thalamus (clustering coefficient: TD > OI, mTBI, d = 0.66 to 0.68). Both mTBI and OI demonstrated reduced global and regional network efficiency and segregation as compared to TD children. Findings suggest a general effect of childhood injury that could reflect pre‐ and postinjury factors that can alter brain structure. An OI group provides a more conservative comparison group than TD children for structural neuroimaging research in pediatric mTBI.     

脑白质病变与轻度认知功能障碍的关系

目的 探讨脑白质病变(WML)与轻度认知功能障碍(MCI)的关系.方法 71例WML患者根据头颅MRI检查分为轻度组(27例)、中度组(21例)、重度组(23例),39例无WML的对照者为对照组.对入组者进行神经心理学量表检查;比较各组MCI的患病率,分析WML与MCI的相关性.结果 WML轻、中、重度组的MCI患病率明显高于对照组(均P＜0.01);WML中、重度组简易精神状态检查(MMSE)及蒙特利尔认知评估量表(MoCA)评分显著低于WML轻度组和对照组(均P＜0.01);随着WML程度的加重,除了抽象能力评分,MoCA其他各认知领域的评分均显著降低(均P＜0.05).多元线性相关分析显示,WML程度与MMSE、MoCA总分及除抽象思维能力的各认知域评分呈负相关(r=-0.252 ～-0.782,均P＜0.01).结论 WML可导致MCI,其对认知功能障碍的影响与WML的程度有关.     

Normal-appearing white and grey matter damage in MS

Abstract The aims of this study were to improve, using a 3.0 Tesla (T) scanner and diffusion tensor (DT) magnetic resonance imaging (MRI) with sensitivity encoding, our understanding of: 1) the possible pathological substrates of normal-appearing white matter (NAWM) and grey matter (GM) damage in multiple sclerosis (MS) and 2) the factors associated to WM and GM atrophy in this condition. Conventional and DT MRI of the brain were acquired from 32 relapsing-remitting (RR) MS patients and 16 controls. Lesion load, WM (WMV), overall GM (GMV), and neocortical GM (NCV) volumes were measured. NAWM mean diffusivity (MD) and fractional anisotropy (FA), and GM MD were calculated. GMV and NCV were lower (p ≤ 0.001) in MS patients than controls, whereas WMV did not differ significantly. MS patients had higher NAWM and GM average MD and lower NAWM average FA (p ≤ 0.001) than controls. Moderate correlations were found between intrinsic lesion and tissue damage with both GM volumetric and diffusivity changes ()0.41 ≤ r ≤ 0.42, p ≤ 0.04). DT MRI and volumetry measurements at 3.0 T confirm the presence of NAWM and GM abnormalities in RRMS patients. Although histopathology was not available, axonal and neuronal damage and consequent reactive glial proliferation are the most likely substrates of the changes observed.     

Review: The long‐term consequences of microglial activation following acute traumatic brain injury

The brain is vulnerable to a number of acute insults, with traumatic brain injury being among the commonest. Neuroinflammation is a common response to acute injury and microglial activation is a key component of the inflammatory response. In the acute and subacute phase it is likely that this response is protective and forms an important part of the normal tissue reaction. However, there is considerable literature demonstrating an association between acute traumatic brain injury to the brain and subsequent cognitive decline. This article will review the epidemiological literature relating to both single and repetitive head injury. It will focus on the neuropathological features associated with long‐term complications of a single blunt force head injury, repetitive head injury and blast head injury, with particular reference to chronic traumatic encephalopathy, including dementia pugilistica. Neuroinflammation has been postulated as a key mechanism linking acute traumatic brain injury with subsequent neurodegenerative disease, and this review will consider the response to injury in the acute phase and how this may be detrimental in the longer term, and discuss potential genetic factors which may influence this cellular response. Finally, this article will consider future directions for research and potential future therapies.     

Pulsed arterial spin labeling effectively and dynamically observes changes in cerebral blood flow after mild traumatic brain injury

Cerebral blood flow is strongly associated with brain function, and is the main symptom and diagnostic basis for a variety of encephalopathies. However, changes in cerebral blood flow after mild traumatic brain injury remain poorly understood. This study sought to observe changes in cerebral blood flow in different regions after mild traumatic brain injury using pulsed arterial spin labeling. Our results demonstrate maximal cerebral blood flow in gray matter and minimal in the white matter of patients with mild traumatic brain injury. At the acute and subacute stages, cerebral blood flow was reduced in the occipital lobe, parietal lobe, central region, subcutaneous region, and frontal lobe. Cerebral blood flow was restored at the chronic stage. At the acute, subacute, and chronic stages, changes in cerebral blood flow were not apparent in the insula. Cerebral blood flow in the temporal lobe and limbic lobe diminished at the acute and subacute stages, but was restored at the chronic stage. These findings suggest that pulsed arterial spin labeling can precisely measure cerebral blood flow in various brain regions, and may play a reference role in evaluating a patient's condition and judging prognosis after traumatic brain injury.     

Persistent CO2 reactivity deficits are associated with neurological dysfunction up to one year after repetitive mild closed head injury in adolescent mice

Cerebrovascular reactivity (CVR) deficits in adolescents with concussion may persist after resolution of neurological symptoms. Whether or not CVR deficits predict long term neurological function is unknown. We used adolescent mice closed head injury (CHI) models (54 g, 107 cm or 117 cm drop height), followed by blood oxygenation level dependent (BOLD)-functional MRI with CO₂ challenge to assess CVR and brain connectivity. At one week, 3HD 107 cm mice showed delayed BOLD responses (p = 0.0074), normal striatal connectivity_, and an impaired respiratory rate response to CO₂ challenge (p = 0.0061 in ΔRmax). The 107 cm group developed rotarod deficits at 6 months (p = 0.02) and altered post-CO₂ brain connectivity (3-fold increase in striatum to motor cortex correlation coefficient) by one year, but resolved their CVR and respiratory rate impairments, and did not develop cognitive or circadian activity deficits. In contrast, the 117 cm group had persistent CVR (delay time: p = 0.016; washout time: p = 0.039) and circadian activity deficits (free-running period: 23.7 hr in sham vs 23.9 hr in 3HD; amplitude: 0.15 in sham vs 0.2 in 3HD; peak activity: 18 in sham vs 21 in 3HD) at one year. Persistent CVR deficits after concussion may portend long-term neurological dysfunction. Further studies are warranted to determine the utility of CVR to predict chronic neurological outcome after mild traumatic brain injury.     

Novel‐graded traumatic brain injury model in rats induced by closed head impacts

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Due to the heterogeneity of human TBI, none of the available animal models can reproduce the entire spectrum of TBI. This study was designed to develop a novel‐graded TBI rat model which is induced by closed head impacts (CHI) with reproducible brain damage and neurological dysfunction. A total of 75 male Sprague–Dawley rats (200 ± 20 g) were randomly equally divided into five groups: the Sham, 0.5, 0.6, 0.7 and 0.8 MPa groups. A custom‐made, air‐driven injury apparatus was used to induce CHIs (from 0.5 to 0.8 MPa). The kinematic parameters during the procedure were recorded by a force sensor and a high‐speed camera. Mortality rate, duration of unconsciousness (latency period of righting reflex), modified neurological severity score (mNSS) and whole brain water content (BWC) were examined. Pathological changes were evaluated by hematoxylin‐eosin (HE) stain and immunohistochemical stain for amyloid precursor protein (APP). The impact force and speed were 785.3 ± 14.12 N and 5.71 m/s in the 0.5 MPa group, 837.72 ± 10.41 N and 6.06 m/s in the 0.6 MPa group, 857.65 ± 11.11 N and 6.25 m/s in the 0.7 MPa group, and 955.6 ± 16.35 N and 6.67 m/s in the 0.8 MPa group. The periods of loss of righting reflex in 0.6–0.8 MPa groups were significantly higher than that in the Sham group. The mNSS score and BWC of the 0.8 MPa group remained higher 24 h after injury than other groups. Brain damage was indicated by increased APP expression in TBI rats. In conclusion, the newly developed CHI rat model was a highly controlled and reproducible graded TBI model, and provided a useful tool to investigate the underlying mechanism and therapeutic effects of TBI with various injury severities.     

Age‐related changes in the topological organization of the white matter structural connectome across the human lifespan

Lifespan is a dynamic process with remarkable changes in brain structure and function. Previous neuroimaging studies have indicated age‐related microstructural changes in specific white matter tracts during development and aging. However, the age‐related alterations in the topological architecture of the white matter structural connectome across the human lifespan remain largely unknown. Here, a cohort of 113 healthy individuals (ages 9–85) with both diffusion and structural MRI acquisitions were examined. For each participant, the high‐resolution white matter structural networks were constructed by deterministic fiber tractography among 1024 parcellation units and were quantified with graph theoretical analyses. The global network properties, including network strength, cost, topological efficiency, and robustness, followed an inverted U‐shaped trajectory with a peak age around the third decade. The brain areas with the most significantly nonlinear changes were located in the prefrontal and temporal cortices. Different brain regions exhibited heterogeneous trajectories: the posterior cingulate and lateral temporal cortices displayed prolonged maturation/degeneration compared with the prefrontal cortices. Rich‐club organization was evident across the lifespan, whereas hub integration decreased linearly with age, especially accompanied by the loss of frontal hubs and their connections. Additionally, age‐related changes in structural connections were predominantly located within and between the prefrontal and temporal modules. Finally, based on the graph metrics of structural connectome, accurate predictions of individual age were obtained (r = 0.77). Together, the data indicated a dynamic topological organization of the brain structural connectome across human lifespan, which may provide possible structural substrates underlying functional and cognitive changes with age. Hum Brain Mapp 36:3777–3792, 2015. © 2015 Wiley Periodicals, Inc.     

Differences in grey and white matter atrophy in amnestic mild cognitive impairment and mild Alzheimer's disease

Background:  Grey matter (GM) atrophy has been demonstrated in amnestic mild cognitive impairment (aMCI) and mild Alzheimer's disease (AD), but the role of white matter (WM) atrophy has not been well characterized. Despite these findings, the validity of aMCI concept as prodromal AD has been questioned.
Methods:  We performed brain MRI with voxel-based morphometry analysis in 48 subjects, aiming to evaluate the patterns of GM and WM atrophy amongst mild AD, aMCI and age-matched normal controls.
Results:  Amnestic mild cognitive impairment GM atrophy was similarly distributed but less intense than that of mild AD group, mainly in thalami and parahippocampal gyri. There were no difference between aMCI and controls concerning WM atrophy. In the mild AD group, we found WM atrophy in periventricular areas, corpus callosum and WM adjacent to associative cortices.
Discussion:  We demonstrated that aMCI might be considered a valid concept to detect very early AD pathology, since we found a close proximity in the pattern of atrophy. Also, we showed the involvement of WM in mild AD, but not in aMCI, suggesting a combination of Wallerian degeneration and microvascular ischaemic disease as a plausible additional pathological mechanism for the discrimination between MCI and AD.     

Depressive symptoms and white matter changes in patients with dementia

OBJECTIVE: The aim of the present study was to investigate if depressive symptoms in demented patients are associated with white matter changes (WMCs) in the brain. BACKGROUND: WMCs are frequently found in patients with dementia, as well as among elderly nondemented patients with depressive symptoms. However, it is less established whether or not WMCs are related to depressive symptoms in demented patients. METHODS: 67 (26 men, 41 women) patients with primary degenerative dementia (Alzheimer's disease, frontotemporal dementia), vascular dementia (VaD), or mixed Alzheimer/VaD dementia were included in the study. The patients were young-old (mean 68.1, SD 7.3). All patients underwent a standardized examination procedure and MRI of the brain. The degree of WMCs was visually rated, blindly. Depressive symptoms were rated according to the Gottfries-Br?ne-Steen scale (anxiety, fear-panic, depressed mood). RESULTS: No significant relationship was found between WMCs and depressive symptoms in the demented patients. CONCLUSION: The possible involvement of WMCs in the pathogenesis of depressive symptoms in dementia is unclear. A link between disruptions of frontal-subcortical pathways, due to WMCs, and depressive symptomatology in dementia has been hypothesised from earlier findings, which would imply common elements of pathogenesis for depressive symptomatology and cognitive impairment in dementia. However, the results of the present study do not add further support to this hypothesis.     

Electroencephalogram and evoked potential parameters examined in Chinese mild head injury patients for forensic medicine

1 Introduction Concussion is both the most common and most puz- zling type of mild traumatic brain injury (MTBI), with its nature still under drastic debate now[1]. Though the cogni- tive and memory functions were impaired in humans[2], thekey research focus is on the “miserable minority”[3] who suffer from acute concussion that is often presented with a variety of persistent physical, emotional, and cognitive symptoms. It is uncertain if these post concussional syn- dromes (PCS) are gene…     

Electroencephalogram and evoked potential parameters examined in Chinese mild head injury patients for forensic medicine

Objective To evaluate the usefulness of quantitative electroencephalogram （QEEG）, flash visual evoked potential （F-VEP） and auditory brainstem responses （ABR） as indicators of general neurological status. Methods Comparison was conducted on healthy controls （N=30） and patients with brain concussion （N=60） within 24 h after traumatic brain injury. Follow-up study of patient group was completed with the same standard paradigm 3 months later. All participants were recorded in multi-modality related potential testing in both early and late concussion at the same clinical setting. Glasgow coma scale, CT scanning, and physical examinations of neuro-psychological function, optic and auditory nervous system were performed before electroencephalogram （EEG） and evoked potential （EEG-EP） testing. Any participants showed abnormal changes of clinical examinations were excluded from the study. Average power of frequency spectrum and power ratios were selected for QEEG testing, and latency and amplitude of F-VEP and ABR were recorded. Results Between patients and normal controls, the results indicated： （1） Highly significance （P 〈 0.01） in average power of α1 and power ratios of θ/α1, 0/α2, α1/α2 of EEG recording; （2） N70-P 100 amplitude of F-VEP in significant difference at early brain concussion; and （3） apparent prolongation of Ⅰ～Ⅲ inter-peak latency of ABR appeared in some individuals at early stage after concussion. The follow-up study showed that some patients with concussion were also afflicted with characteristic changes of EEG components for both increments of α1 average power and θ/α2 power ratio after 3 months recording. Conclusion EEG testing has been shown to be more effective and sensitive than evoked potential tests alone on detecting functional state of patients with mild traumatic brain injury （MTBI）. Increments of α1 average power and θ/α2 power ratio are the sensitive EEG parameters to determining early concussion and evaluating outcome of postconcussion symptoms （PCS）. Follow-up study associated with persistent PCS may be consistent with the postulate of substantial biological, rather than psychological origin. The study suggests that combination of EEG and EP parameters can contribute to the evaluation of brain function as a whole for clinical and forensic applications.     

A fixel‐based analysis of micro‐ and macro‐structural changes to white matter following adult traumatic brain injury

Diffusion tensor imaging is often used to assess white matter (WM) changes following traumatic brain injury (TBI), but is limited in voxels that contain multiple fibre tracts. Fixel‐based analysis (FBA) addresses this limitation by using a novel method of analysing high angular resolution diffusion‐weighted imaging (HARDI) data. FBA examines three aspects of each fibre tract within a voxel: tissue micro‐structure (fibre density [FD]), tissue macro‐structure (fibre‐bundle cross section [FC]) and a combined measure of both (FD and fibre‐bundle cross section [FDC]). This study used FBA to identify the location and extent of micro‐ and macro‐structural changes in WM following TBI. A large TBI sample (N_mild = 133, N_{moderate–severe} = 29) and control group (healthy and orthopaedic; N = 107) underwent magnetic resonance imaging with HARDI and completed reaction time tasks approximately 7 months after their injury (range: 98–338 days). The TBI group showed micro‐structural differences (lower FD) in the corpus callosum and forceps minor, compared to controls. Subgroup analyses revealed that the mild TBI group did not differ from controls on any fixel metric, but the moderate to severe TBI group had significantly lower FD, FC and FDC in multiple WM tracts, including the corpus callosum, cerebral peduncle, internal and external capsule. The moderate to severe TBI group also had significantly slower reaction times than controls, but the mild TBI group did not. Reaction time was not related to fixel findings. Thus, the WM damage caused by moderate to severe TBI manifested as fewer axons and a reduction in the cross‐sectional area of key WM tracts.     

BDNF expression increases without changes in play behavior following concussion in juvenile rats (Rattus Norvegicus)

ABSTRACT

Purpose: Young children have a high risk of concussion or mild traumatic brain injury (mTBI). Children often appear healthy soon after mTBI, but some have pervasive cognitive and/or motor impairments. Understanding underlying mechanisms recruited after concussion may help for return to play protocols and mitigating what might be lifelong impairments. Methods: We investigated molecular and behavioral changes in a rat model of childhood concussion. Rats received an injury or sham procedure at an age approximately equivalent to the human period of early childhood. Social play was analyzed for behavioral differences. Tissue from the right motor cortex (impacted), left motor cortex, and medial prefrontal cortex were analyzed for brain derived neurotrophic factor (BDNF) protein. Results: Play behavior was not significantly different between conditions. BDNF levels were much higher in both the right and left motor cortices of the mTBI group compared to medial prefrontal cortex, which is relatively remote from the impact site, within the mTBI group and all tissue collected from the sham group. Conclusions: There is ongoing plastic change at the cellular level in both the impacted area and the well-connected contralateral area after a concussion, suggesting compensatory mechanisms after injury are still at play.